Chemosensors are used in a wide variety of measurements, from assaying components of a bodily fluid in a doctor's office to locating explosives in an airport. Arrays of sensors are of great utility, as they allow the detection of a large number of different species, or the high fidelity recognition of analytes using a large number of sensors of low selectivity. Data from a large array of chemical sensors can be analyzed to detect the presence or activity of particular chemical compounds or functional groups. Two-dimensional arrays are currently being used as biosensors in the medical field to screen for genetic and viral diseases. Many of these arrays include thousands of polynucleotides of known gene sequences on a small chip to detect for specific genes which are turned on or off in a particular cell line (Sapolsky et al. Genetic Analysis: Biomolecular Engineering 14:187-192, 1999; Lockhart Nature Medicine 4:1235-1236, 1998; Fodor FASEB J. 11:A879, 1997; Fodor Science 277:393-395, 1997; each of which is incorporated herein by reference). However, as these chips become larger and larger, the readout of the chip becomes increasingly time-consuming and cost intensive, and more sophisticated instrumentation is required to analyze the array. Even today, the expense and complexity of reading a chip is beyond what can reasonably be used in a doctor's office.
Many chemosensors used today undergo a change in an optical property such as absorbance or fluorescence upon binding of a chemical compound. Therefore, optical fibers are ideally suited to carry light to and from such optical chemosensors. Optical fiber bundles with a sensor placed at the end of each fiber are currently being developed by Illumina, Inc.
Combinatorial Chemistry and Drug Discovery
Combinatorial chemistry is another area of research where a large number of chemical compounds must be analyzed. The techniques of combinatorial chemistry allow the synthesis of thousands to millions of chemical compounds which may subsequently be screened in the search for new pharmaceutical agents, new catalysts, new chemosensors, or other materials with desired properties (Geysen et al. Molec. Immunol. 23:709-715, 1986; Houghton et al. Nature 354:84-86, 1991; Frank Tetrahedron 48:9217-9232, 1992; Bunin et al. Proc. Natl. Acad. Sci. USA 91:4708-4712, 1994; Thompson et al. Chem. Rev. 96:555-600, 1996; Keating et al. Chem. Rev. 97:449-472, 1997; Gennari et al. Liebigs Ann./Recueil 637-647, 1997; Reddington et al. Science 280:1735-1737, 1998; each of which is incorporated herein by reference). Before the advent of combinatorial chemistry, potential compounds were typically identified by laborious extraction and screening of natural products or by intricate, single-molecule syntheses.
In the preparation of a combinatorial library of chemical compounds, thousands to millions of compounds are synthesized on a small scale. The process usually starts with a core structure having several sites for functionalization and derivatization. Each of these sites is reacted under a variety of conditions with known reagents to yield a large number of products. The library may be synthesized by various methods, including the split-and-pool method and the parallel synthesis method. The synthetic steps may take place in solution or on a solid phase support, as is more commonly used (Lam et al. Chem. Rev. 97:411448, 1997; Nefzi et al. Chem. Rev. 97:449-472, 1997; Gennari et al. Liebigs Ann./Recueil 637-647, 1997; Gravert et al. Chem. Rev. 97:489-509, 1997; Thompson et al. Chem. Rev. 96:555-600, 1996; Accts. Chem. Res. 29, 1996 (special issue on combinatorial chemistry); Pirrung et al. Chem. Rev. 97:473-488, 1997; Czarnik Curr. Opin. Chem. Biol. 1:60, 1997; each of which is incorporated herein by reference). The resulting library is then screened using a known assay to identify compounds with a desired activity. The structure of the identified compound can then be determined, for example by decoding information on a solid support (Czarnik Proc. Natl. Acad. Sci. USA 94:12738-12739, 1997; Brenner et al. Proc. Natl. Acad. Sci. USA 89:5381-5283, 1992; Ohlmeyer et al. Proc. Natl. Acad. Sci. USA 90:10922-10926, 1993; U.S. Pat. No. 5,565,324; each of which is incorporated herein by reference) or by determining the compound's position in a spatially addressable array (Fodor et al. Science 251:767-773, 1991; U.S. Pat. No. 5,143,854; U.S. Pat. No. 5,547,839; Geysen et al. Molec. Immunol. 23:709-715, 1986; Houghton et al. Nature 354:84-86, 1991; each of which is incorporated herein by reference). The identified compound may be used as a lead compound in the development of pharmaceutical agents. However, the synthesis and analysis of an entire library, which may contain millions of compounds, is very time consuming and costly, and full scale library analysis is rarely done.
A method and system allowing for fully parallel synthesis of a combinatorial library and full scale analysis of the library would be very useful in the search for new pharmaceutical agents and other compounds with a variety of properties.